Having graduated from the Moscow University (1913), Trubetzkoy delivered lectures there until the Revolution. Thereafter he moved first to the University of Rostov-on-Don, then to the University of Sofia (1920–22), and finally took the chair of Professor of Slavic Philology at the University of Vienna (1922–1938). He died from a heart attack attributed to Nazi persecution following his publishing an article highly critical of Hitler's theories.

Trubetzkoy's chief contributions to linguistics lie in the domain of phonology, in particular in analyses of the phonological systems of individual languages and in the search for general and universal phonological laws. His magnum opus, Grundzüge der Phonologie (Principles of Phonology),[2] was issued posthumously. In this book he famously defined the phoneme as the smallest distinctive unit within the structure of a given language. This work was crucial in establishing phonology as a discipline separate from phonetics.

It is sometimes hard to distinguish Trubetzkoy's views from those of his friend Roman Jakobson, who should be credited with spreading the Prague School views on phonology after Trubetzkoy's death.